Lipid metabolism and the risk factors of cardiovascular disease: Implication of dietary omega-3 polyunsaturated fatty acids

Cardiovascular disease (CVD) is a complicated and multifarious disease, and is the number one cause of mortality worldwide. The pathogenesis of CVD is attributed to the interaction between genetics and environment. There are numerous data that support the cardioprotective properties of omega (n)-3 polyunsaturated fatty acids (PUFA); however, there are also controversial reports. Considering the reported sex and age differences in the pathophysiology of CVD and the metabolism of n-3 PUFA, it is imperative to consider these factors in the cardioprotective effects of n-3 PUFA. The current thesis investigated the effects of n-3 PUFA on the risk factors of CVD, such as dyslipidemia and obesity, with a particular focus on how sex, age, and dose of n-3 PUFA affect lipid and lipoprotein metabolism. The plasma concentrations of lipids and lipoproteins of C57BL/6 mice offspring at weaning and 16 weeks postweaning were chosen as study outcomes to assess the sex, age, and dose-specific effects of n-3 PUFA on markers of dyslipidemia, a well-known risk factor of CVD. A longer exposure to a postnatal diet high in n-3 PUFA increased plasma concentration of low-density lipoprotein (LDL) cholesterol in the offspring in a sex-specific manner; however, the profile of this increase was less atherogenic, as the high n-3 PUFA group had a lower plasma concentration of very small LDL particles in both males and females. There was no effect of high n-3 PUFA diet observed on plasma concentration of high-density lipoprotein cholesterol; however, the high n-3 PUFA group had a higher cholesterol efflux in the male offspring but not in female offspring. Lipidomic analyses revealed that high n-3 PUFA diet led to higher hepatic and plasma concentrations of n-3 PUFA- containing bioactive lipids, such a phosphatidylcholine, lysophosphatidylcholine and free fatty acids, which could positively influence pathways involved in cardioprotection. The effects of dietary n-3 PUFA on obesity at the cellular level was also investigated, using adipocyte hypertrophy as the outcome measure of adipose tissue enlargement. A diet high in n-3 PUFA prevented adipocyte hypertrophy in males, with no effect in females. High n-3 PUFA diet also led to the downregulation of the messenger RNA expression of acyl-CoA:diacylglycerol acyltransferase 2, fatty acid binding protein-4, peroxisome proliferator- activated receptor protein ÷, and leptin in males, which are key proteins involved in adipocyte hypertrophy; however, no effect was observed in females. The last study assessed the effects of dose and duration of exposure to dietary n-3 PUFA on docosa- hexaenoic acid accretion in the brain, and the expression of neurotrophins known to have neuroprotective and cardioprotective benefits. Dietary n-3 PUFA led to an age-dependent increase in the expression of brain-derived neurotrophic factor, tropomyosin receptor kinase, and phosphorylated cyclic AMP response element binding protein. In conclusion, the results from the current thesis demonstrate a sex-, dose-, and age-specific effect of n-3 PUFA on risk factors of CVD, and on novel regulatory pathways by which n-3 PUFA could reduce dyslipidemia and obesity. The results also suggest that n-3 PUFA could be neuroprotective and cardioprotective through a common neurotrophin signalling pathway.